The overall mean testosterone levels fall within the normal range (13.08±9.68 nmol/l for TT and 0.202±0.08 nmol/l for FT). When stratified using local laboratory guidelines, 20 patients were found to be testosterone deficient for serum TT and 17 patients for FT.
Agreement between serum free testosterone and salivary testosterone levels
Figure 2 shows the agreement between calculated serum FT measurements and laboratory measurements of ST.
The Bland–Altman plot for agreement between ST and FT measures shows a bias of 0.087 nmol/l with an SD of 0.056 nmol/l. This results in a +2 SD of 0.104 nmol/l and a −2 SD of −0.122 nmol/l (95% LoA). The calculated coefficient of variation is 0.12 nmol/l.
Reproducibility of repeated measures of salivary testosterone
Figure 3 details the reproducibility of repeated measurement of ST over the two separate HF clinic visits (minimum of 4 weeks and a maximum of 4 months between repeated measures).
The Bland–Altman plot for the agreement between repeated ST measurements demonstrates a bias of 0.0137 nmol/l with an SD of 0.021 nmol/l. This results in a +2 SD of 0.041 nmol/l and −2 SD of −0.041 nmol/l (95% LoA). The calculated coefficient of variation is 0.042 nmol/l.
Reproducibility of repeated measures of serum free testosterone
Figure 4 details the reproducibility of repeated measurements of FT over two separate clinic visits taken in conjunction with ST measurements mentioned previously and with the same timescales (i.e. minimum difference of 4 weeks and maximum of 4 months).
The Bland–Altman plot for agreement between repeated measures of FT shows a bias between FT measurements of 0.004 nmol/l (SD±0.0025 nmol/l). Therefore, the mean difference±2 SD or 95% LoA is +0.055 nmol/l and −0.046 nmol/l. The coefficient of repeatability is 0.0050 nmol/l.
Correlation between salivary testosterone and traditional serum testosterone parameters
Table 2 indicates that there is a strong positive correlation between ST and traditionally collected serum measurements of testosterone (TT and BioT, P<0.001). The calculated coefficient of determination between ST and TT is 0.74 and between ST and BioT is 0.63.
Correlation between salivary testosterone and traditionally collected serum testosterone parameters with exercise capacity
Table 3 shows the Pearson’s correlation between measures of testosterone and 6 min walk exercise capacity.
Table 3 shows moderately strong correlations between ST, FT and BioT and the overall 6 min walk distance (P<0.001). TT correlates more strongly than the other three parameters (r=0.878, P<0.001). The calculated coefficient of determination for exercise distance and ST is 0.63, FT is 0.56, TT is 0.72 and BioT is 0.36.
Correlation between salivary testosterone and traditionally collected serum testosterone parameters with cardiac functional/structural parameter
Table 4 shows the correlation between collected testosterone parameters and indices of LA structure, function and mechanics.
There were no significant correlations between ST levels nor any traditional measure of testosterone and detailed indices of LA structure and function in a male HF population.
Table 5 shows the correlation between collected testosterone parameters and indices of LV structure, function and mechanics.
There were no significant correlations between ST nor any traditional measure of testosterone and detailed indices of LV structure and function.
Table 6 shows the correlation between collected testosterone parameters and indices of right heart structure, function and mechanics.
There are no significant correlations between ST nor any traditional measure of testosterone and detailed indices of right heart structure and function.
Correlation of salivary testosterone and traditionally collected serum testosterone parameters with quality of life outcomes
Table 7 shows the correlation between collected testosterone parameters and indices of health-specific and disease-specific quality of life.
ST and FT demonstrate moderate correlations with the general health domain of SF-36 (r=0.402 and 0.466, respectively, P=0.04, following Holm–Bonferroni adjustment). All testosterone fractions apart from BioT correlated strongly and significantly with physical function, BioT demonstrating a more moderate correlation (r=0.597, P<0.001). Moderately strong correlations were observed between all testosterone fractions and the role physical and physical summary domains (all Ps<0.001). The calculated coefficients of determination between ST and FT, and the SF-36 domain of general health were 0.16 and 0.22, respectively. The coefficients of determination between ST, FT, TT and BioT, and SF-36 role physical were 0.49, 0.49, 0.44 and 0.33, SF-36 physical function were 0.65, 0.65, 0.73 and 0.36, and SF-36 physical summary were 0.47, 0.55, 0.55 and 0.50, respectively.
This is the first study to assess the relationship between ST levels and traditional serum testosterone levels and the relationship between ST and important health outcomes in men with HF. ST levels correlated strongly and positively (P<0.001) with TT and BioT. Bland–Altman analysis revealed close agreement between ST and FT, reinforcing the concept that ST represents the free fraction of testosterone in HF patients. ST correlated well with many important health outcomes in HF patients, including exercise capacity and important aspects of quality of life.
ST sampling as an alternative to TT sampling is a novel application in HF patients. ST has been established to represent the free fraction of testosterone 14, and exogenous administration of testosterone results in ST increases in parallel with serum TT increases, without significant alteration in SHBG binding capacity 27. Bland–Altman plots between ST and FT confirm that this hypothesis upholds in HF patients. There was a small bias of 0.087 nmol/l between ST and FT values (SD of 0.056 nmol/l), resulting in an excellent calculated coefficient of variation of 0.12 nmol/l. Correlation studies also show that ST levels relate strongly and positively to TT and BioT levels in a HF population, with highly significant ρ-values following adjustment for multiple comparisons (0.861 and 0.792, respectively). In addition to this, basic cost analysis using local healthcare tariffs in the host biochemistry laboratory has shown that the total cost per patient for measurement of ST is around £20 per patient. Serum FT analysis is reported to be three times more costly due to the greater amount of preparation time and staff experience required for its analysis. As such, ST could be considered a more cost-effective measurement, given the close relationship with FT observed in the present study.
TT is reported to be at its lowest before 10:00 a.m. 28. Testosterone levels vary markedly throughout a 24-h period 29,30, with ∼30% of deficient men sampled during the afternoon showing normal testosterone concentrations earlier during the day 28. In this study, testosterone fractions were collected between 08:15 and 09:45 h. For accuracy, participants provided separate samples at their next hospital appointment, which ranged between 4 weeks and 4 months after initial testosterone sampling. Bland–Altman analysis of repeated ST and FT measurements demonstrated excellent reproducibility without deviation from a laboratory low to normal concentration during this time period. There was no appreciable difference in the reproducibility of repeated measurements of FT when compared with ST. This statement is reflected by visualization of graphical data with no formal statistical test performed.
There is a strong positive correlation between testosterone fractions and endurance capacity. TT levels appear to be more correlated with exercise capacity (r=0.848, coefficient of determination 0.72). However, the observed difference between TT and ST and FT is negligible (r=0.792, coefficients of determination 0.63 and 0.751, coefficient of determination 0.56, respectively). BioT shows a weaker relationship with endurance capacity (r=0.598, coefficient of determination 0.36) but remains modest and significant following α-level adjustment. The coefficient of determination is lower (0.36) compared with other testosterone components.
Other research has indicated that TT deficiency detrimentally impacts exercise performance in HF patients, showing significant correlations with peak oxygen uptake 9,31 and 6-min walk distance 8. These findings are consistent with the associations observed in elderly men without clinical evidence of HF 32. Improved exercise capacity in HF patients, associated with higher levels of TT, may be due to altered cardiac function 8,9. This hypothesis has been formulated on the basis that TT is inversely correlated with both LV and RV ejection fraction (EF%) 9, and supplementation has been shown to improve indices of cardiac function in animal and human models 6,32. Our study does not support this hypothesis. It is feasible that our study was underpowered to detect such relationships between testosterone and cardiac function; however, the lack of a trend towards a possible relationship between the data suggests that this is unlikely.
Although studies have clearly reported relationships between testosterone concentration and indices of cardiac function 8,32, there is also ample research evidence to suggest that testosterone does not modulate cardiac mechanics despite improvements in exercise capacity in a similar cohort of patients 33. There are some factors other than sample size that may explain the lack of a relationship observed in this study. All patients in the current study had severely impaired LV systolic function (mean ejection fraction 28.31±7.07%), with the majority (55%) being of ischaemic origin. The pathological nature of ischaemic LV systolic dysfunction (particularly following acute myocardial infarction) may serve to diminish the expected correlation between function and testosterone level. For instance, regional myocardial scarring and fibrosis due to ischaemia rarely show improvement in contractility over time and as such, may negate the expected change in function depending on the testosterone level. In relation to this, many parameters pertaining to cardiac mechanics (e.g. strain imaging, twist, untwist, etc.) would be adversely altered in the presence of regional myocardial scarring.
Another important confounder that may ameliorate possible relationships between cardiac function and testosterone relates to the medical therapy prescribed to the study cohort. Almost all patients were administering angiotensin converting enzyme inhibitor inhibitors, β-blockers, diuretics and statins. There is definitive published evidence showing that statin therapy can adversely alter testosterone concentration, particularly in an aged population 34, and this, together with the combined effects of β-blockade and angiotensin converting enzyme inhibitor inhibition, on cardiac function may diminish the expected relationship between testosterone and cardiac function.
A section of patients were found to be in atrial fibrillation at the time of echocardiography (20%). It is a widely held notion that many diastolic parameters of cardiac function are less accurate with coexistent atrial fibrillation – particularly when associated with dilated left atria and a raised LA pressure. These factors may have also had a bearing on the relationships obtained. To further this concept, the inherent limitations of many of the echocardiographic parameters collected in a fairly obese population, with the possibility of diminished image quality and off-plane measurements (mean BMI 27.02±3.97 kg/m2), may have also adversely affected the testosterone–cardiac function relationship.
In support of the above practical limitations, clinical trial echocardiographic guidance suggests measurement of LV ejection fraction on the basis of LV volumes obtained by the method of discs 35. Limitations arise when the apex is foreshortened, the endocardium is inadequately viewed and there is limitation by reliance on only two LV planes. Longitudinal velocity assessment using PW Doppler can also be limited by a number of factors. PW Doppler assessment of tissue movement is only able to provide information on a specific point of the myocardium determined by sample volume positioning, components perpendicular to the ultrasound beam remain unknown and there is significant angle dependency. TDI velocities may also be influenced by global heart motion, movement of adjacent structures and also blood flow 36. Two-dimensional speckle tracking echocardiography demonstrates technical limitations. In more obese populations with limited images, it is possible that endocardial border tracking may be inaccurate. Two-dimensional speckle tracking echocardiography is also limited in patients with acoustic shadowing or reverberations 36. Tracking software algorithms use a-priori knowledge of ‘normal’ LV function and, as such, there may be errors when assessing regional abnormalities or when assessing neighbouring segments 36.
Testosterone may act at the vascular or skeletal muscle level to promote an increase in walking performance. No vascular nor muscular parameters were measured as part of this study, and future research should aim to address these possibilities. Testosterone levels can impact endothelial function 37, skeletal muscle mass and the local synthesis of growth factors (IGF 1) and of contractile proteins 38. Low testosterone levels can also adversely affect other physiological systems including lung function 39, baroreflex sensitivity and autonomic imbalance 31, levels of circulating inflammatory cytokines found to impede LV contractility and muscular performance 32 and skeletal muscle perfusion 40.
Correlation analysis showed that FT and ST correlate modestly with the general health domain of SF-36 (r=0.402 and.466, respectively). Importantly, the coefficients of determination for this relationship are relatively low at 0.16 and 0.22, respectively, suggesting that this correlation is relatively weak. TT and BioT also demonstrated a modest correlation, which did not reach significance. There were, however, moderately strong, significant correlations between all fractions of testosterone and the physical domains of SF-36, supported by a modest coefficient of determination for the role physical domain (0.49 for ST and FT, 0.44 for TT and 0.33 for BioT). Coefficients of determination for physical function were slightly improved (0.64 for ST, 0.65 for ST, 0.73 for TT), apart from that for BioT, which was modest (0.36). Modest coefficients of determination were observed for the physical summary domain (0.47 ST, 0.55 FT, 0.55 TT and 0.50 BioT). No significant relationships were observed between testosterone and the mental domains of the SF-36 or MLHFQ/BDI scores. Testosterone-deficient elderly men receiving supplementation have been shown to have a significantly improved overall quality of life, as assessed using the SF-12 questionnaire, when compared with those receiving placebo 41. Logically, the significant relationships between exercise capacity and testosterone concentration in this study could translate to improved overall perception of physical and mental quality of life in relation to the overall testosterone level. However, this has not always been the case. Malkin et al. 6 observed no improvement in the general health score following testosterone supplementation in HF patients despite significant improvements in exercise capacity.
During this study, no relationships were seen between BDI or MLHFQ score and testosterone concentration. This is in contradiction to other research, which has shown that low levels of circulating anabolic hormones resulted in increased severity of depressive symptoms in young men with HF 42. The same authors were unable to replicate this improvement in depressive symptoms in an older population, a finding similar to that of this study. Clinically, all participants in our study were stable HF patients. This may, in part, explain the lack of observed correlations with HF-specific quality of life (MLHFQ).
Testosterone deficiency has been associated with the metabolic syndrome and can be predictive of weight gain, central obesity, hypertension, insulin resistance and type II diabetes 43. Research has also showed that in men with HF, testosterone supplementation can improve fasting insulin sensitivity and also reduce body mass 44. It is feasible, that insulin resistance may have promoted decreased exercise capacity and indirectly resulted in alterations to physical related quality of life, due to related deleterious effects on skeletal muscle metabolism 45. Further reports have suggested that insulin resistance may further deteriorate cardiac performance in HF patients, due to cellular disruption of cardiac metabolism 46. Blood samples were not taken for fasting insulin nor glucose assessment. Hence, the impact of insulin resistance on exercise tolerance in our cohort of patients is unknown. This warrants further investigation.
Carrying out multiple correlation statistical analysis during this study, it is plausible that we have elevated the chances of incurring a type I error. To correct for this, we applied simultaneous inference to control the familywise error rate. This technique 26 is more powerful than Bonferroni adjustment and can reduce the type I error rate. Another important facet when analysing correlation studies is to recognize that the ρ-value is a more complete representation of the relationship than the α-value itself. Care must be taken to understand that our statistics represent a relationship between fractions of testosterone and some important health outcomes in a HF model, and that they do not imply a cause and effect. The coefficient of determination was calculated to express data as a percentage. Therefore, the percentage of total variation of variable ‘x’ can be accounted for by variation of variable ‘y’. This technique allows our study to provide a more conservative measure of the relationship between two variables, seldom reported by other researchers in correlation studies.
ST was found to have excellent agreement with FT, together with an excellent level of repeatability, which was consistent with traditional FT serum sampling. We noted a strong positive correlation between ST and serum testosterone levels, which may be modulated by circulating proteins, particularly in an elderly HF population with numerous comorbidities. In addition, basic cost analysis was in favour of ST over FT, given the additional time and experience required for serum FT analysis. There were important relationships between all fractions of testosterone and important health outcomes in a HF population. Future research should aim to build upon this work by attempting to understand the mechanistic physiology behind the observed relationships and to achieve a suitable sample size to ascertain a valid ‘cutoff’ range for ST. One could ascertain that this study shows that a valid cutoff for ST could be equal to FT values given the closeness of their relationship in our HF cohort. ST can be used as a marker of FT in HF patients and provides an opportunity to avoid semi-invasive blood sampling, the inherent inaccuracies of FT calculations from specified formulae and the associated costs of ‘gold-standard’ analysis of FT.
Conflicts of interest
There are no conflicts of interest.
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Keywords:Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
exercise; free testosterone; heart failure; quality of life; salivary testosterone